Molecular basis of arrhythmic substrate in ageing murine peroxisome proliferator-activated receptor γ co-activator deficient hearts modelling mitochondrial dysfunction.

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Edling, Charlotte E 
Fazmin, Ibrahim T 
Saadeh, Khalil 
Chadda, Karan R 
Ahmad, Shiraz 

INTRODUCTION: Ageing and chronic metabolic disorders are associated with mitochondrial dysfunction and cardiac pro-arrhythmic phenotypes which were recently attributed to slowed atrial and ventricular action potential (AP) conduction in peroxisome proliferator-activated receptor γ co-activator deficient (Pgc-1β-/-) mice. METHODS: We compared expression levels of voltage-gated Na+ channel (NaV1.5) and gap junction channels, Connexins 40 and 43 (Cx40 and Cx43) in the hearts of young and old, and wild-type (WT) and Pgc-1β-/- mice. This employed Western blotting (WB) for NaV1.5, Cx40 and Cx43 in atrial/ventricular tissue lysates, and immunofluorescence (IF) from Cx43 was explored in tissue sections. Results were analysed using two-way analysis of variance (ANOVA) for independent/interacting effects of age and genotype. RESULTS: In atria, increased age and Pgc-1β-/- genotype each independently decreased both Cx40 and Cx43 expression without interacting effects. In IF experiments, both age and Pgc-1β deletion independently reduced Cx43 expression. In ventricles, age and genotype exerted interacting effects in WB studies of NaV1.5 expression. Young Pgc-1β-/- then showed greater NaV1.5 expression than young WT ventricles. However, neither age nor Pgc-1β deletion affected Cx43 expression, independently or through interacting effects in both WB and IF studies. CONCLUSION: Similar pro-arrhythmic atrial/ventricular phenotypes arise in aged/Pgc-1β-/- from differing contributions of altered protein expression and functional effects that may arise from multiple acute mechanisms.

cardiac arrhythmia, connexins, voltage-gated channels, Aging, Animals, Arrhythmias, Cardiac, Connexin 43, Connexins, Disease Models, Animal, Gene Expression Regulation, Heart, Heart Rate, Humans, Metabolic Diseases, Mice, Mitochondria, NAV1.5 Voltage-Gated Sodium Channel, PPAR gamma, Phenotype
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Biosci Rep
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Portland Press Ltd.
Wellcome Trust (093680/Z/10/Z)
Medical Research Council (MR/M001288/1)
British Heart Foundation (None)
Wellcome Trust (105727/Z/14/Z)
British Heart Foundation (PG/15/12/31280)